1. Field of the Invention
This invention relates to compounds that are antagonists of MCP-1 function, to compositions containing them, and to methods for their use.
2. Description of the Related Art
U.S. application Ser. No. 10/060,967 (published as PCT International Publication No. WO 02/060900 on 8 Aug. 2002 and as U.S. Patent Application Publication No. 2003/0096705 on 22 May 2003) discloses compounds of formula I and formula II: where:    Y is O, S or N—R7,    Z is N or C—R8,    R1, R2, R3, and R8 are independently, hydrogen, or optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), halo(lower alkyl), —CF3, halogen, nitro, —CN, —OR9, —SR9, —NR9R10, —NR9(carboxy(lower alkyl)), —C(═O)R9, —C(═O)OR9, —C(═O)NR9R10, —OC(═O)R9, —SO2R9, —OSO2R9, —SO2NR9R10, —NR9SO2R10 or —NR9C(═O)R10, wherein R9 and R10 are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C1-2 alkyl)2, lower independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C1-2 alkyl)2, lower alkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionally substituted aryl, optionally substituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R9 and R10 together are —(CH2)4-6— optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionally substituted C1-2 alkyl) group,    R7 is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), —C(═O)R9, —C(═O)OR9, —C(═O)NR9R10, —SO2R9, or —SO2NR9R10, wherein R9 and R10 are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C1-2 alkyl)2, lower alkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionally substituted aryl, optionally substituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R9 and R10 together are —(CH2)4-6— optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionally substituted C1-2 alkyl) group,    R4 and R5 are independently, hydrogen, lower alkyl optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted aryl(lower alkyl), or, together, are —(CH2)2-4—,    R6 is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aryl(lower alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl(lower alkyl), —C(═O)R11, —C(═O)OR11, —C(═O)NR11R12, —SO2R11, or —SO2NR11R12, wherein R11 and R12 are independently, hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), aryl, optionally substituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R11 and R12 together are —(CH)4-6—, and the pharmaceutically acceptable salts thereof, optionally in the form of single stereoisomers or mixtures of stereoisomers thereof.
The application also discloses the synthesis of these compounds, pharmaceutical compositions comprising them, and methods for their use. The compounds are described as antagonists of MCP-1 (monocyte chemoattractant protein-1, also referred to as MCAF, macrophage/monocycte chemotactic and activating factor) function, useful in the prevention and treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as atherosclerosis, Crohn's disease, diabetic nephropathy, inflammatory bowel disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, rheumatoid arthritis, and transplant rejection. The compounds are also described as useful in the prevention and treatment of allergic hypersensitivity disorders, especially those characterized by basophil activation and eosinophil recruitment such as allergic rhinitis and asthma.